The normal function of the mammalian kidney includes such activity as maintaining a constant acid-base and electrolyte balance, removing excess fluids and removing undesirable products of the body's metabolism from the blood. In an individual with end stage renal disease, this functioning of the kidney may be reduced to as low as 5% or less of the normal level. When renal function has decreased to this point, artificial means must then be employed to substitute for the kidney activity, if life is to be sustained. This is accomplished clinically by the use of dialysis. One of the most common methods for achieving this is hemodialysis, in which the patient's blood is passed through an artificial kidney dialysis machine. In the machine, a synthetic non-permeable membrane acts as an artificial kidney with which the patient's blood is contacted on one side; on the opposite side of the membrane is a dialyzing fluid or dialysate, the composition of which is such that the undesirable products in the patient's blood will naturally pass across the membrane by diffusion, into the fluid. The blood is thus cleansed, in essentially the same manner as the kidney would have done, and the blood is returned to the patient's body. This method of dialysis requires the patient to be physically "hooked up" to the machine for several hours, often several times a week. For obvious reasons, this technique, although efficient, presents a number of inconveniences.
Some of the disadvantages associated with hemodialysis, which requires extracorporeal treatment of the blood, are overcome by the use of techniques which utilize the patient's own peritoneum as the required semipermeable membrane. The peritoneum is the membraneous lining of the body cavity which contains large numbers of blood vessels and capillaries and is thus capable of acting as a natural semipermeable membrane. Dialysis solution is introduced into the peritoneal cavity, via a catheter in the abdominal wall. A suitable period of residence time for the dialysate is allowed to permit the exchange of solutes between it and the blood; fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate to permit water outflow from the blood. Thus, the proper acid-base, electrolyte and fluid balance is returned to the blood and the dialysis solution is simply drained from the body cavity through the catheter. Although more than one type of peritoneal dialysis exists, the technique known as continuous ambulatory peritoneal dialysis (CAPD) is particularly favored, since it does not require the patient to remain tied to machinery while the solute and fluid exchange is accomplished. The only sedentary period required is during infusion and draining of the dialysis solution.
One of the most difficult aspects of peritoneal dialysis, and yet one of the most important, is finding a suitable osmotic agent for inclusion in the dialysate, by which the required osmotic gradient would be achieved. By osmotically active agent, as used herein, is meant a substance present in the dialysis solution which is capable of maintaining the osmotic gradient required to cause transport of water and toxic substances across the peritoneum into the dialysis solution. The appropriate agent should fulfill at least two critical criteria. First, it must be, to a greater or lesser extent biologically inert, i.e., non-toxic and yet metabolizable, and second, should preferably not rapidly cross the peritoneal membrane into the blood; this would allow maintenance of the maximum ultrafiltration gradient, and also would prevent toxicity or accumulation of unwanted substances in the blood. Absence of toxicity is particularly important, since nearly any substance placed in the peritoneum will eventually find its way into the circulation, whether by a slow lymphatic drain, or by dialysis across the peritoneal membrane. To date, no known substance has completely satisfied these needs, although a number of different materials have been used with varying success. The agent which has currently achieved the most widespread acceptance is glucose. Glucose has the advantage of being non-toxic, and is so readily metabolizable if it enters the blood. The major problem with its use, however, is that it is readily taken up into the blood from the dialysate. Although, as noted above, any substance will eventually find its way into the circulation, glucose crosses the peritoneum so rapidly that the osmotic gradient is broken down within 2-3 hours of infusion. This may even cause a reversal of the direction of ultrafiltration, causing the unwanted result of water being reabsorbed from the dialysate toward the end of the time allowed for exchange. Further, the amount of glucose which is taken in may represent a large proportion of the patient's energy intake, possibly being as high as 12-35%; while this does not significantly affect a non-diabetic patient, it can be a severe metabolic burden to a patient whose glucose tolerance is already impaired. This added burden may be implicated in the hyperglycemia and obesity, observed in a number of CAPD patients. Diabetic patients suffer from the further inconvenience and risk of having to add insulin to the peritoneal dialysate, in order to reduce the risks of hypoglycemina resulting from the added glucose load.
Use of glucose also presents problems in the preparation of the dialysate. Sterilization of the dialysate is typically accomplished by heating which, at physiological pH, will cause glucose to caramelize. To compensate for this, the pH of the dialysate is usually adjusted to within the pH range of 5.0-5.5. This low pH, so far below that which is normal for the body, may be responsible for the pain experienced by some patients on inflow, and could also cause sclerosis of the peritoneal membrane, which will in turn cause a decrease in solute clearance (Schmidt, et al., Arch. Int. Med., 141: 1265-1266, 1980).
These disadvantages make the finding of a suitable alternative to glucose as an osmotic agent highly desirable. A number of substances have been proposed to meet the criteria of being biologically inert, not readily crossing the peritoneal membrane, being non-toxic and exerting adequate osmotic pressure a flow concentrations. To date, none of the suggested materials has proven to be an adequate substitute for glucose. For example, the use of dextrans (Gjessing, Acta Med. Scan., 185: 237-239, 1960) or polyanions (U.S. Pat. No. 4,339,433) has been proposed because of their high molecular weight, which should minimize their diffusion across the peritoneum into the blood. However, the role of the lymphatic system in the process of solute transport apparently limits the advantages of the high molecular weight per se (Allen, et al., Amer. J. Physiol., 119: 776-782, 1937). Also, with respect to the polyanions, it is unclear as to what the toxic effects of these would be, since most are non-metabolizable. Similar problems with metabolism are observed with compounds such as sorbitol, xylitol and glucose polymers. Sorbitol which is very slowly metabolized has been associated with instances of hyperosmolar coma and death (Raja, et al., Ann. Int. Med., 73: 993-994, 1970), and is no longer used. Both xylitol and glucose polymers also have a tendency to accumulate in the blood, and may be associated with unpleasant side effects (Bazyato, et al., Trans Amer. Soc. Artif. Interm. Organs, 28: 280-286, 1982). Fructose, which is comparable to glucose in its osmotic capacity, also exhibits many of the same disadvantages; because of its higher cost, it has not achieved widespread use.
More promising is the proposed use of amino acids to replace glucose. Amino acids are well-tolerated, with no known adverse side effects (Oren, et al., Perit. Dial. Bull, 3: 66-72). Because of their lower molecular weight, they exert a higher osmotic effect, on a mass basis, than glucose. This also probably results, however, in a more rapid uptake into the blood, causing a rapid loss of osmotic gradient. Although, unlike glucose, amino acid uptake may be beneficial, in that it may compensate for the protein loss observed in many CAPD patients, there is a considerable disadvantage in the almost prohibitive costs of amino acid solutions when compared with glucose. Furthermore, the rapid uptake of amino acids results in a considerable nitrogen burden, with a significant increase in blood urea nitrogen levels. Thus, it appears that even amino acids do not provide the appropriate substitutes.
The present invention, however, now provides improvement in the method for peritoneal dialysis which employs an osmotic agent which is not only a safe and beneficial alternative to glucose, but which also is economically feasible. It has now been unexpectedly discovered that a mixture of relatively low molecular weight oligopeptides (300-2000 daltons) derived from the enzymatic hydrolysis of a high quality protein, such as whey protein, may be used as an effective osmotic agent in a peritoneal dialysis solution; in comparison with an amino acid solution, the somewhat higher molecular weight of the peptides prevents the rapid uptake into the blood, allowing a more effective maintenance of the osmotic gradient as well as preventing the unwanted increase of nitrogen in the blood. The peptide mixture, which is ultimately, although very slowly, absorbed into the serum further provides a valuable dietary supplement, being derived from high-quality protein. Finally, the present peptide mixture provides an inexpensive and easily obtainable source of osmotic agent. Other peptide mixtures, used for medicinal purposes, have been previously described. For example, U.S. Pat. No. 4,427,658 describes a protein hydrolysate derived from enzymatic hydrolysis of whey protein. In that case, nearly total enzymatic hydrolysis was claimed to be performed, with no separation of larger from smaller peptides. Therefore, the resulting product apparently contains peptides of much larger sizes, possibly up to 5000 daltons or more, in the final mixture. These may pose antigenic and/or allergic risks since pinocytotic uptake from the peritoneum to the blood is known. This is significantly different from the carefully separated, relatively low molecular weight mixtures of the present invention.